The present invention relates to aminoacid esters of 6-alpha- and 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides, pharmaceutically-acceptable salts thereof, conventional esters thereof which are hydrolyzable in vivo, bis-methanediol esters thereof; or mixed methanediol esters with said beta-lactamase inhibitors and sulbactam (penicillanic acid 1,1-dioxide), said methanediol esters also hydrolyzable in vivo. While some of these compounds possess antibacterial activity per se, their principal value is as beta-lactamase inhibitors. Thus they are useful in combination with conventional beta-lactam antibiotics (penicillins and cephalosporins) against microorganisms resistant or partially resistant to beta-lactam antibiotics through production of beta-lactamase enzymes. Also encompassed by the present invention are pharmaceutical compositions comprising a present beta-lactamase inhibiting compound and a conventional beta-lactam antibiotic; mixed bis-methanediol esters of the present beta-lactamase inhibiting compounds and a conventional beta-lactam antibiotic; pharmaceutical compositions of the latter mixed esters; methods of treating bacterial infections with either of the above pharmaceutical compositions; and compounds useful as intermediates in the preparation of these various compounds.
Related compounds, viz, penicillanic acid 1,1-dioxide and esters thereof readily hydrolyzable in vivo (Barth, U.S. Pat. No. 4,234,579); the bis-methanediol ester of sulbactam (Bigham, U.S. Pat. No. 4,309,347); various 6-alpha- and 6-beta-(hydroxymethyl)penicillanic acid 1,1-dioxides and esters thereof (Kellogg, European Patent Application No. 83,977; Kellogg, U.S. Pat. No. 4,287,181); and 6-alpha- and 6-beta-(aminoalkyl)penicillanic acid 1,1-dioxides (Barth, European Patent Application No. 84,925) have been previously described as beta-lactamase inhibitors useful in combination with beta-lactam antibiotics for the treatment of bacterial infections. Antibacterial bis-esters of methanediol with penicillins and penicillanic acid 1,1-dioxide (Bigham, U.S. Pat. No. 4,244,951; Godtfredsen et al., U.S. Pat. No. 4,342,772) have also been described. Talampicillin (USAN generic name), the 1H-isobenzofuran-3-on-1-yl ester of ampicillin, and (5-methyl-1,3-dioxol-3-on-4-yl)methyl ester of ampicillin (Sakamoto et al., U.S. Pat. No. 4,342,693) exemplify two in vivo hydrolyzable ester radicals of particular interest in the present case.
U.K. Patent Application No. 2,076,812 broadly discloses beta-lactamase inhibiting compounds of the formula ##STR1## wherein R.sup.x is carboxy or protected carboxy, R.sup.y is hydroxy, etherified hydroxy (R.sup.z O--) or esterified hydroxy (e.g., R.sup.z COO--), and R.sup.z is an optionally substituted hydrocarbon radical, thereby defining literally an infinite number of compounds. Since ethers wherein the group R.sup.z is a 1-aminoalkyl group are not formed by known methods, and would not be stable even if they could be formed, the definition of R.sup.z cannot be construed to include alkyl groups substituted in the 1-position with amino, alkylamino or dialkylamino groups.